The hemagglutinating and hemolytic properties of antibodies to blood group antigens are affected by the nature and distribution of the antigenic determinants on the erythrocyte membrane. Erythrocytes prepared with known numbers of antigen sites have allowed a clearer understanding of this relationship. Red cells coupled with hapten (sulfanilic acid or DNP) groups have demonstrated that a threshold number of sites is required for hemagglutination and hemolysis, and that the titer of antibodies tested with these cells is proportional to the antigen site density. A preliminary classification of blood group antibodies has been developed from these data and the differential effects of antigen distribution on IgG and IgM antibodies has been clarified. Extension of these studies will consider the effect of the nature of the antigenic determinant, the effect of membrane charge, and the effect of separation of antigen from membrane surface. The dynamics of antibody-cell interaction will be considered as will the binding properties of intact antibody molecules, fragments, and subunits. These studies are part of a long-term investigation of the immunologic aspects of red cell destruction. Definition of the patterns of antibody- erythrocyte interaction are a necessary first step toward this goal.